The appropriate wiring of neurons in the brain requires appropriate migration and placement of cortical neurons. Neuronal migration and the resultant placement of neurons provide the framework for the emergence of neuronal connectome or functional wiring. Area specific and neuronal type specific defects in neuronal migration and the subsequent changes in neuronal connectivity is an underlying cause of a wide spectrum of neurological disorders, including autism, schizophrenia, epilepsy, mental retardation, and malformations such as lissencephaly, schizencephaly, microencephaly, and macro/microgyria. However, very little is known about how distinct classes of neurons coordinately navigate from their sites of birth to their final laminar and areal specific destinations in the developing cerebral cortex. Understanding how the different types of cortical neurons migrate at the right time in right numbers to appropriate cortical areas will be essential to understand the pathogenic mechanisms that underlie neurodevelopmental and neuropsychiatric disorders. We therefore aim to define how cortical neurons (i.e., projection neurons and interneurons) achieve their appropriate placement in the cerebral cortex. Towards this goal, we will develop methods for real time, 4-D confocal and multiphoton imaging of genetically defined subtypes of cortical neurons in the developing brain. Using this approach, we will map how distinct classes of cortical neurons navigate through the developing cerebral wall to arrive at their appropriate areal and laminar positions. Together, this comprehensive mapping of coordinated migration and placement of interneurons and projection neurons during cerebral cortical development will define the neuronal blueprint used to form brain connectome, facilitate the development of new in vivo live embryonic brain imaging methods, help delineate the basis of brain abnormalities in a spectrum of neurodevelopmental disorders, and thus will generate transformative insights into normal and aberrant brain development. PUBLIC HEALTH RELEVANCE: Very little is known about how distinct classes of neurons coordinately navigate from their sites of birth to their final laminar and areal specific destinations in the developing cerebral cortex. Disruption of this process, resulting from genetic mutations or environmental insults, is an underlying cause of a wide spectrum of neurological disorders, including autism, schizophrenia, epilepsy, mental retardation, and malformations such as lissencephaly, schizencephaly, microencephaly, and macro/microgyria. Therefore, understanding how the different types of cortical neurons migrate at the right time in right numbers to appropriate cortical areas will be essential to understand the pathogenic mechanisms that underlie neurodevelopmental and neuropsychiatric disorders. This knowledge could help identify and rationalize novel targets for therapeutic interventions for these disorders.